The mechanisms and molecules controlling the identity of renin-expressing cells are unknown. Recently, we described a novel gene, termed Zis (for Zinc finger, splicing) which encodes for a remarkably conserved protein with structural characteristics (Zn-fingers, NLS, SR-rich region), physiological regulation, and developmental pattern of expression that suggest its role in the regulation of renin cell identity. During early mouse embryonic development (E12), renin- expressing cells originate from and are present in the undifferentiated metanephric mesenchyme. Later in fetal life, renin cells are found along intrarenal arteries, in glomeruli, and among interstitial cells. With maturation, renin cells become restricted to the classical adult juxtaglomerular (JG) localization. Expression of Zis follows a similar developmental pattern with higher levels in newborn than adult kidney. When purified JG cells are cultured for 2 days, they express Zis, and synthesize and release renin. If an adult animal is subjected to manipulations that threaten homeostasis, there is an increase in the number of renin-expressing cells (due to metaplasia of preexisting cells) along preglomerular arteries, interstitium and glomeruli resembling the embryonic pattern. Again, this is accompanied by increased Zis expression. The aforementioned findings demonstrate that adult kidney cells retain the plasticity to develop phenotypic characteristics of renin-expressing cells and suggest that the ability of adult cells to (re)acquire the renin cell phenotype depends on the lineage and developmental history of the cell(s) involved. Our central hypothesis is that Zis is involved renin cell specification. The present proposal will test whether: 1) Expression of Zis is necessary for JG cell differentiation and nephrovascular development 2) renin cell progenitors give rise to arteriolar smooth muscle cells, pericytes, and mesangial cells 3) Zis is required for metaplastic transformation of those cells into renin-expressing cells. The proposed studies should generate fundamental new knowledge on renin cell specification and the phenomenon of recruitment/metaplastic transformation, a crucial mechanism that controls hormone availability and thus blood pressure and fluid/electrolyte homeostasis. The proposed work has the potential to open new avenues for the understanding, prevention and treatment of hypertension and kidney diseases.